Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Petrovsky National Research Centre of Surgery, |
RCV000851391 | SCV000930665 | likely pathogenic | Marfan syndrome | 2019-08-01 | criteria provided, single submitter | clinical testing | The p.Cys2390Ser has been reported in individual with MFS (PMID:17663468), and was absent from large population studies. Other substitution (p.Cys2390Arg) has been previously reported in the ClinVar (rs397515847, variation ID:42421) with Likely pathogenic classification. Prediction tools like NetGene2, Provean, SIFT, PolyPhen2 show a damaging result for p.Cys2390Ser. According to revised Ghent nosology one of the criteria for causal FBN1 mutation is missense variants affecting/creating cysteine residues (doi:10.1136/jmg.2009.072785). Basing on above-mentioned evidences we evaluate the p.Cys2390Ser variant as likely pathogenic. Functional study deemed necessary. |
Invitae | RCV003768621 | SCV004570919 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 2390 of the FBN1 protein (p.Cys2390Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 31825148). ClinVar contains an entry for this variant (Variation ID: 690431). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant disrupts the p.Cys2390 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 33059708; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |